Posted by Dave on January 23, 2013
by Jonathan Latham and Allison Wilson,
How should a regulatory agency announce they have discovered something potentially very important about the safety of products they have been approving for over twenty years?
In the course of analysis to identify potential allergens in GMO crops, the European Food Safety Authority (EFSA) has belatedly discovered that the most common genetic regulatory sequence in commercial GMOs also encodes a significant fragment of a viral gene ( Podevin and du Jardin 2012). This finding has serious ramifications for crop biotechnology and its regulation, but possibly even greater ones for consumers and farmers. This is because there are clear indications that this viral gene (called Gene VI) might not be safe for human consumption. It also may disturb the normal functioning of crops, including their natural pest resistance.
Cauliflower Mosaic Virus
What Podevin and du Jardin discovered is that of the 86 different transgenic events (unique insertions of foreign DNA) commercialized to-date in the United States 54 contain portions of Gene VI within them. They include any with a widely used gene regulatory sequence called the CaMV 35S promoter (from the cauliflower mosaic virus; CaMV). Among the affected transgenic events are some of the most widely grown GMOs, including Roundup Ready soybeans (40-3-2) and MON810 maize. They include the controversial NK603 maize recently reported as causing tumors in rats ( Seralini et al. 2012).
The researchers themselves concluded that the presence of segments of Gene VI "might result in unintended phenotypic changes". They reached this conclusion because similar fragments of Gene VI have already been shown to be active on their own (e.g. De Tapia et al. 1993). In other words, the EFSA researchers were unable to rule out a hazard to public health or the environment.
In general, viral genes expressed in plants raise both agronomic and human health concerns (reviewed in Latham and Wilson 2008). This is because many viral genes function to disable their host in order to facilitate pathogen invasion. Often, this is achieved by incapacitating specific anti-pathogen defenses. Incorporating such genes could clearly lead to undesirable and unexpected outcomes in agriculture. Furthermore, viruses that infect plants are often not that different from viruses that infect humans. For example, sometimes the genes of human and plant viruses are interchangeable, while on other occasions inserting plant viral fragments as transgenes has caused the genetically altered plant to become susceptible to an animal virus (Dasgupta et al. 2001). Thus, in various ways, inserting viral genes accidentally into crop plants and the food supply confers a significant potential for harm.
The Choices for Regulators
The original discovery by Podevin and du Jardin (at EFSA) of Gene VI in commercial GMO crops must have presented regulators with sharply divergent procedural alternatives. They could 1) recall all CaMV Gene VI-containing crops (in Europe that would mean revoking importation and planting approvals) or, 2) undertake a retrospective risk assessment of the CaMV promoter and its Gene VI sequences and hope to give it a clean bill of health.
It is easy to see the attraction for EFSA of option two. Recall would be a massive political and financial decision and would also be a huge embarrassment to the regulators themselves. It would leave very few GMO crops on the market and might even mean the end of crop biotechnology.
Regulators, in principle at least, also have a third option to gauge the seriousness of any potential GMO hazard. GMO monitoring, which is required by EU regulations, ought to allow them to find out if deaths, illnesses, or crop failures have been reported by farmers or health officials and can be correlated with the Gene VI sequence. Unfortunately, this particular avenue of enquiry is a scientific dead end. Not one country has carried through on promises to officially and scientifically monitor any hazardous consequences of GMOs (1).
Unsurprisingly, EFSA chose option two. However, their investigation resulted only in the vague and unreassuring conclusion that Gene VI "might result in unintended phenotypic changes" (Podevin and du Jardin 2012). This means literally, that changes of an unknown number, nature, or magnitude may (or may not) occur. It falls well short of the solid scientific reassurance of public safety needed to explain why EFSA has not ordered a recall.
Can the presence of a fragment of virus DNA really be that significant? Below is an independent analysis of Gene VI and its known properties and their safety implications. This analysis clearly illustrates the regulators' dilemma.
The Many Functions of Gene VI
Gene VI, like most plant viral genes, produces a protein that is multifunctional. It has four (so far) known roles in the viral infection cycle. The first is to participate in the assembly of virus particles. There is no current data to suggest this function has any implications for biosafety. The second known function is to suppress anti-pathogen defenses by inhibiting a general cellular system called RNA silencing (Haas et al. 2008). Thirdly, Gene VI has the highly unusual function of transactivating (described below) the long RNA (the 35S RNA) produced by CaMV (Park et al. 2001). Fourthly, unconnected to these other mechanisms, Gene VI has very recently been shown to make plants highly susceptible to a bacterial pathogen (Love et al. 2012). Gene VI does this by interfering with a common anti-pathogen defense mechanism possessed by plants. These latter three functions of Gene VI (and their risk implications) are explained further below:
1) Gene VI Is an Inhibitor of RNA Silencing
RNA silencing is a mechanism for the control of gene expression at the level of RNA abundance (Bartel 2004). It is also an important antiviral defense mechanism in both plants and animals, and therefore most viruses have evolved genes (like Gene VI) that disable it (Dunoyer and Voinnet 2006).
Gene VI (upper left) precedes the start of the 35S RNA
This attribute of Gene VI raises two obvious biosafety concerns: 1) Gene VI will lead to aberrant gene expression in GMO crop plants, with unknown consequences and, 2) Gene VI will interfere with the ability of plants to defend themselves against viral pathogens. There are numerous experiments showing that, in general, viral proteins that disable gene silencing enhance infection by a wide spectrum of viruses (Latham and Wilson 2008).
2) Gene VI Is a Unique Transactivator of Gene Expression
Multicellular organisms make proteins by a mechanism in which only one protein is produced by each passage of a ribosome along a messenger RNA (mRNA). Once that protein is completed the ribosome dissociates from the mRNA. However, in a CaMV-infected plant cell, or as a transgene, Gene VI intervenes in this process and directs the ribosome to get back on an mRNA (reinitiate) and produce the next protein in line on the mRNA, if there is one. This property of Gene VI enables Cauliflower Mosaic Virus to produce multiple proteins from a single long RNA (the 35S RNA). Importantly, this function of Gene VI (which is called transactivation) is not limited to the 35S RNA. Gene VI seems able to transactivate any cellular mRNA (Futterer and Hohn 1991; Ryabova et al. 2002). There are likely to be thousands of mRNA molecules having a short or long protein coding sequence following the primary one. These secondary coding sequences could be expressed in cells where Gene VI is expressed. The result will presumably be production of numerous random proteins within cells. The biosafety implications of this are difficult to assess. These proteins could be allergens, plant or human toxins, or they could be harmless. Moreover, the answer will differ for each commercial crop species into which Gene VI has been inserted.
Straight to the Source: Independent Science News.